Aromatic nitrogen-containing 6-membered cyclic compounds

ABSTRACT

An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I):                    
     wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R 1  is a substituted or unsubstituted lower alkyl group, —NH—Q—R 3  (R 3  is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond), or —NH—R 4  (R 4  is a substituted or unsubstituted cycloalkyl group); R 2  is a substituted or unsubstituted aryl group; one of Y and Z is ═CH—, and the other is ═N—, or a pharmaceutically acceptable salt thereof, these compounds exhibiting excellent selective PDE V inhibitory activities, and hence, being useful in the prophylaxis or treatment of penile erectile dysfunction, etc.

This application is a divisional of application Ser. No. 09/925,892,which is a continuation application of PCT international application No.PCT/JP00/06258 which has an international filing date of Sep. 13, 2000which designated the United States, the entire contents of both of whichare incorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel aromatic nitrogen containing6-membered cyclic compound exhibiting a cGMP specific phosphodiesterase(PDE) inhibitory activity (PDE V inhibitory activity) and being usefulas a medicament, and a process for preparing the same.

BACKGROUND ART

In general, it is known that cGMP, which is an intracellular secondmessenger, is decomposed and inactivated by phosphodiesterase whichwidely distributes in many cell types and tissues of the living body,and when said PDE activity is inactivated, the level of cGMP in cells isincreased, and as a result, various pharmacological activities, forexample, relaxation of vascular smooth muscle, relaxation of bronchialsmooth muscle, and inhibition of platelet aggregation are exhibited.

Moreover, it has been reported that such cGMP specific PDE inhibitors(i.e., PDE V inhibitors) are useful in the treatment of diseases causedby a functional disorder of cGMP-signaling, including hypertension,angina pectoris, myocardial infarction, chronic or acute heart failure,pulmonary hypertension, etc. (cf., PCT Patent Publication WO 96/05176,etc.), and prostatic hyperplasia (Australian Patent Publication No.9955977). It has also been reported that PDE V inhibitors may be usefulin the treatment of female sexual dysfunction (Vemulapalli et al., LifeSciences, 67, 23-29 (2000)), diabetic gastroparesis (Watkins et al., J.Clin. Invest. 106: 373-384 (2000)), achalasia (Bortolotti et al.,Gastroenterology; 118: 253-257 (2000)), diarrhea (Mule et al., Br. J.Pharmacol., 127, 514-520 (1999)), constipation (Bakre et al., J. Cell.Biochem. 77: 159-167 (2000)) and asthma (Turner et al., Br. J.Pharmacol., 111, 1198-1204 (1994)).

Furthermore, it has been also reported that1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazine [general name:Sildenafil] having PDE V inhibitory activity is useful in the treatmentof diseases such as penile erectile dysfunction (copulative impotence),etc. (cf., Boolell et al., The Journal of Urology, Supplement, vol. 155,no. 5, p. 495A739 (1996); Terrett et al., Bioorganic & MedicinalChemistry Letters, vol. 6, no. 15, p. 1819 (1996); and Ballard et al.,British Journal of Pharmacology, Proceeding Supplement, vol. 118, p. 153(1996)).

However, sildenafil has been reported to have side effects such asheadache, facial suffusion, gut disorder, rhinitis, color sensedisorder, penile erectile continuance, etc. (Irwin et al., The NewEngland Journal of Medicine, vol. 338, no. 20, p. 1397-1404 (1998);Morales et al., International Journal of Impotence Research, vol. 10,no. 2, p. 69-73 (1998); and Goldenberg, Clinical Therapeutics, vol. 20,no. 6, p. 1033-1048 (1998)).

In addition, sildenafil has also been reported that the effects ofsildenafil on light response of retina tissues and its PDE VI inhibitoryactivity correlate each other in the experiments on dogs (Morales etal., International Journal of Impotence Research, vol. 10, no. 2, p.69-73 (1998)), while it has been reported that PDE VI on retina plays animportance role in the sensation of light (Morrales et al.,International Journal of Impotence Research, vol. 10, no. 2, p. 69-73(1998); Estrade et al., European Journal of Pharmacology, vol. 352, p.157-163 (1998)).

DISCLOSURE OF INVENTION

An object of the present invention is to provide a novel aromaticnitrogen-containing 6-membered cyclic compound showing an excellentphosphodiesterase V (PDE V) inhibitory activity, and being useful as aremedy for the prophylaxis or treatment of penile erectile dysfunctionwith few side effects. Another object of the present invention is toprovide a process for preparing such a novel aromaticnitrogen-containing 6-membered cyclic compound.

The present invention relates to an aromatic nitrogen-containing6-membered cyclic compound of the formula (I):

wherein Ring A is a substituted or unsubstituted nitrogen-containingheterocyclic group; R¹ is a substituted or unsubstituted lower alkylgroup, a group of the formula: —NH—Q—R³ (in which R³ is a substituted orunsubstituted nitrogen-containing heterocyclic group, and Q is a loweralkylene group or a single bond), or a group of the formula: —NH—R⁴ (inwhich R⁴ is a substituted or unsubstituted cycloalkyl group); R² is asubstituted or unsubstituted aryl group; one of Y and Z is a group ofthe formula: ═CH—, and the other is a group of the formula: ═N—, or apharmaceutically acceptable salt thereof, and a process for preparingthe same.

Among the compounds (I) of the present invention, thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5-to 10-membered monocyclic or bicyclic nitrogen-containing heterocyclicgroup, more particularly, a 5- or 6-membered nitrogen-containingheteromonocyclic group and a 8- to 10-membered nitrogen-containingheterobicyclic group, and most particularly, a 5- or 6-memberednon-aromatic nitrogen-containing heteromonocyclic group such aspyrrolidinyl group, piperazinyl group, piperidyl group, morpholinogroup, etc., a 5- or 6-membered aromatic nitrogen-containingheteromonocyclic group such as imidazolyl group, pyrrolyl group, etc.,and a nitrogen-containing heterobicyclic group such as6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl group,5,6,7,8-tetrahydroimidazo[1,2-a]-pyrazin-7-yl group,5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl group,1,2,3,4-tetrahydro-2-isoquinolinyl group,1H-2,3,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl group,4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-6-yl group,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl group,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl group, etc.

The nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is a 5- or6-membered nitrogen-containing heteromonocyclic group or a 8- to10-membered nitrogen-containing heterobicyclic group, for example, a 5-or 6-membered non-aromatic nitrogen-containing heteromonocyclic groupsuch as morpholinyl group, piperazinyl group, piperidyl group,thiadiazolyl group, dihydropyrimidinyl group, dihydropyrazolyl group, a5- or 6-membered aromatic nitrogen-containing heteromonocyclic groupsuch as pyrimidinyl group, pyridazinyl group, pyridyl group, pyrazolylgroup, imidazolyl group, oxazolyl group, thiazolyl group, pyrazinylgroup, and a 8- to 10-membered nitrogen-containing heterobicyclic groupsuch as benzothiazolyl group, quinolyl group, dihydrobenzoxazolyl group,etc.

The substituent of the “substituted or unsubstituted nitrogen-containingheterocyclic group” for Ring A and R³ is, for example, (1) a lower alkylgroup, (2) a hydroxy-substituted lower alkyl group, (3) a formyl group,(4) an oxo group, (5) an amino group, (6) a di-(lower alkyl)amino group,(7) a hydroxy group, (8) a lower alkoxy group, (9) a loweralkoxycarbonyl group, (10) a lower alkoxy-substituted lower alkanoylgroup, (11) a lower alkanoyl group, (12) a cyano-substituted lower alkylgroup, and (13) a pyrimidinyl group substituted by (i) a benzylaminogroup substituted by a halogen atom and a lower alkoxy group and (ii) acycloalkylcarbamoyl group substituted by a hydroxy group, etc.

The aryl group of the “substituted or unsubstituted aryl group” for R²is, for example, a 5- to 10-membered monocyclic or bicyclic aromatichydrocarbon group such as phenyl group, naphthyl group, etc.

The substituent of the “substituted or unsubstituted aryl group” for R²is, for example, a lower alkoxy group, a halogen atom, a cyano group, anitro group, a hydroxy group, a lower alkyl group, etc.

The substituent of the “substituted or unsubstituted lower alkyl group”for R¹ and the substituent of the “substituted or unsubstitutedcycloalkyl group” for R⁴ are, for example, a lower alkoxy group, ahydroxy group, a morpholinyl group, a lower alkylsulfonyl group, adi-(lower alkyl)phosphino group, a di-(lower alkyl)amino group, apyrimidinyl-substituted lower alkylamino group, a pyridyl group, apyridylamino group, a lower alkyl-substituted piperazinyl group, apyrimidinyloxy group, etc.

Throughout the present description and the claims, the “lower alkylgroup” means a straight chain or branched chain alkyl group having 1 to6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, etc. The “lower alkoxy group” means a straightchain or branched chain alkoxy group having 1 to 6 carbon atoms, such asmethoxy, ethoxy, propoxy, isopropyloxy, butyloxy, isobutyloxy,tert-butyloxy, etc.

The “cycloalkyl group” means a cycloalkyl having 3 to 8 carbon atoms,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc. The “lower alkylene group” means a straight chain or branched chainalkylene group having 1 to 6 carbon atoms, such as methylene, ethylene,trimethylene, etc.

The “halogen atom” means a fluorine atom, a chlorine atom, a bromineatom, or an iodine atom.

Among the compounds (I) of the present invention, preferable compoundsare compounds of the formula (I) wherein the nitrogen-containingheterocyclic group of the “substituted or unsubstitutednitrogen-containing heterocyclic group” for Ring A is a 5- or 6-memberednitrogen-containing heteromonocyclic group or a 8- to 10-memberednitrogen-containing heterobicyclic group, and the substituent of theabove “substituted or unsubstituted nitrogen-containing heterocyclicgroup” is selected from the group consisting of (1) a lower alkyl group,(2) a hydroxy-substituted lower alkyl group, (3) a formyl group, (4) anoxo group, (5) an amino group, (6) a hydroxy group, (7) a loweralkoxycarbonyl group, and (8) a pyrimidinyl group substituted by (i) abenzylamino group substituted by a halogen atom and a lower alkoxy groupand (ii) a cycloalkylcarbamoyl group substituted by a hydroxy group, R¹is a lower alkyl group which may optionally be substituted by a groupselected from the group consisting of a lower alkoxy group, a hydroxygroup, a morpholinyl group, a lower alkylsulfonyl group, a di-(loweralkyl)phosphino group, a di-(lower alkyl)amino group, apyrimidinyl-substituted lower alkylamino group, a pyridyl group, apyridylamino group, and a lower alkyl-substituted piperazinyl group, agroup of the formula: —NH—Q—R³, or a group of the formula: —NH—R⁴, thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is a 5- or6-membered nitrogen-containing heteromonocyclic group or a 8- to10-membered nitrogen-containing heterobicyclic group, and thesubstituent of the above “substituted or unsubstitutednitrogen-containing heterocyclic group” is selected from the groupconsisting of a lower alkyl group, a hydroxy-substituted lower alkylgroup, an oxo group, an amino group, a di-(lower alkyl)amino group, alower alkanoyl group and a cyano-substituted lower alkyl group, R⁴ is acycloalkyl group being substituted by a group selected from the groupconsisting of hydroxy group, a lower alkoxy group and a pyrimidinyloxygroup, R² is a phenyl group being substituted by a group selected fromthe group consisting of a lower alkoxy group, a halogen atom, a cyanogroup, a nitro group, a hydroxy group and a lower alkyl group.

More particularly, preferable compounds of the present invention arecompounds of the formula (I), wherein the nitrogen-containingheterocyclic group of the “substituted or unsubstitutednitrogen-containing heterocyclic group” for Ring A is a 5- or 6-memberednitrogen-containing heteromonocyclic group of the formula:

or a nitrogen-containing heterobicyclic group of the following formulawherein the above-mentioned 5- or 6-membered nitrogen-containingheteromonocyclic group and a 5- or 6-membered cyclic group are fused:

and the nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is anon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or an aromatic nitrogen-containing heterocyclic group of the formula:

Among the compounds (I) of the present invention, other preferablecompounds are compounds of the formula (I) wherein thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5-or 6-membered nitrogen-containing heteromonocyclic group or a 8- to10-membered nitrogen-containing heterobicyclic group, and thesubstituent of the above “substituted or unsubstitutednitrogen-containing heterocyclic group” is selected from the groupconsisting of a lower alkyl group, a hydroxy-substituted lower alkylgroup, a formyl group and an oxo group, R¹ is a lower alkyl group whichmay optionally be substituted by a group selected from the groupconsisting of a lower alkoxy group and a morpholinyl group, a group ofthe formula: —NH—Q—R³, or a group of the formula: —NH—R⁴, the“substituted or unsubstituted nitrogen-containing heterocyclic group”for R³ is a 5- or 6-membered nitrogen-containing heteromonocyclic groupwhich may optionally be substituted by a lower alkyl group, R⁴ is acycloalkyl group being substituted by a group selected from the groupconsisting of hydroxy group and a lower alkoxy group, R² is a phenylgroup being substituted by a group selected from the group consisting ofa lower alkoxy group, a halogen atom and a cyano group.

More particularly, preferable compounds of the present invention arecompounds of the formula (I) wherein the nitrogen-containingheterocyclic group of the “substituted or unsubstitutednitrogen-containing heterocyclic group” for Ring A is a 5- or 6-memberednon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or a nitrogen-containing heterobicyclic group of the following formulawherein the above-mentioned 5- or 6-membered non-aromaticnitrogen-containing heteromonocyclic group and a 5- or 6-memberedaromatic nitrogen-containing heteromonocyclic group are fused:

the nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is anon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or an aromatic nitrogen-containing heteromonocyclic group of theformula:

More particularly, preferable compounds of the present invention arecompounds of the formula (I) wherein Ring A is a group of the formula:

R¹ is a lower alkyl group, a lower alkoxy-substituted lower alkyl group,a morpholinyl-substituted lower alkyl group, a group of the formula:—NH—Q—R³, or a group of the formula: —NH—R⁴, R³ is a group of theformula:

R⁴ is a group of the formula:

and R² is a group of the formula:

Among the compounds (I) of the present invention, more preferablecompounds are compounds of the formula (I) wherein thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5-or 6-membered nitrogen-containing heteromonocyclic group or a 8- to10-membered nitrogen-containing heterobicyclic group, and thesubstituent of the above “substituted or unsubstitutednitrogen-containing heterocyclic group” is a group selected from thegroup consisting of a lower alkyl group, a hydroxy-substituted loweralkyl group, a formyl group and an oxo group, R¹ is a loweralkoxy-substituted lower alkyl group, a group of the formula: —NH—Q—R³,or a group of the formula: —NH—R⁴, the “substituted or unsubstitutednitrogen-containing heterocyclic group” for R³ is a 5- or 6-memberednitrogen-containing heteromonocyclic group which may optionally besubstituted by a lower alkyl group, R⁴ is a hydroxy-substitutedcycloalkyl group, and R² is a phenyl group being substituted by a groupselected from the group consisting of a lower alkoxy group and a halogenatom.

More particularly, more preferable compounds of the present inventionare compounds of the formula (I) wherein the nitrogen-containingheterocyclic group of the “substituted or unsubstitutednitrogen-containing heterocyclic group” for Ring A is a 5- or 6-memberednon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or a group of the formula:

the nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is anon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or

an aromatic nitrogen-containing heteromonocyclic group of the formula:

More particularly, more preferable compounds of the present compoundsare compounds of the formula (I) wherein Ring A is a group of theformula:

R¹ is a lower alkoxy-substituted lower alkyl group, a group of theformula: —NH—Q—R³, or a group of the formula: —NH—R⁴, R³ is a group ofthe formula:

R⁴ is a group of the formula:

and R² is a group of the formula:

Among the compounds (I) of the present invention, further preferablecompounds are compounds of the formula (I) wherein thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5-or 6-membered nitrogen-containing heteromonocyclic group or a 8- to10-membered nitrogen-containing heterobicyclic group, and thesubstituent of the above “substituted or unsubstitutednitrogen-containing heterocyclic group” is a hydroxy-substituted loweralkyl group, R¹ is a group of the formula: —NH—Q—R³, the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is a 5- or6-membered nitrogen-containing heteromonocyclic group which mayoptionally be substituted by a lower alkyl group, and R² is a phenylgroup being substituted by a group selected from the group consisting ofa lower alkoxy group and a halogen atom.

More particularly, the more preferable compounds of the presentinvention are compounds of the formula (I) wherein thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5-or 6-membered non-aromatic nitrogen-containing heteromonocyclic group ofthe formula:

or

a group of the formula:

the nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is anon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or

an aromatic nitrogen-containing heteromonocyclic group of the formula:

More particularly, the preferable compounds of the present invention arecompounds of the formula (I), wherein Ring A is a group of the formula:

R¹ is a group of the formula: —NH—Q—R³, R³ is a group of the formula:

and R² is a group of the formula:

Among the compounds (I) of the present invention, the most preferablecompounds are compounds of the formula (I) wherein Y is a group of theformula: ═N—, and Z is a group of the formula: ═CH—.

Among the compounds (I) of the present invention, pharmaceuticallypreferable compounds are compounds selected from the following group ora pharmaceutically acceptable salt thereof.

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine:

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-methoxycyclohexyl)carbamoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-[[(2R)-4-methyl-2-morpholinyl]methyl]carbamoyl]pyrimidine;

2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-[[(2S)-4-methyl-2-morpholinyl]methyl]carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(4-methyl-3-oxo-1-piperazinyl)-4-(3-chloro-4-methoxybenzyl-amino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(4-formyl-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-[cis-2,5-bis(hydroxymethyl)-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-acethylpyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyridazinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-morpholinoethyl)carbonyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-[(4-methyl-2-morpholinyl)methyl]-carbamoyl]pyrimidine;

(S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1pyrrolidinyl)pyrazine;

2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrazine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine;or a pharmaceutically acceptable salt thereof.

Among the compounds (I) of the present invention, pharmaceutically morepreferable compounds are compounds selected from the following group ora pharmaceutically acceptable salt thereof.

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(4-methyl-3-oxo-1-piperazinyl)-4-(3-chloro-4-methoxybenzyl-amino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(4-formyl-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine;or a pharmaceutically acceptable salt thereof.

Among the compounds (I) of the present invention, pharmaceuticallypreferable other compounds are compounds selected from the followinggroup or a pharmaceutically acceptable salt thereof.

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-2-pyrimidinylmethyl)carbamoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine;

(S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine,or a pharmaceutically acceptable salt thereof.

Among the compounds (I) of the present invention, especiallypharmaceutically preferable compounds are compounds selected from thefollowing group or a pharmaceutically acceptable salt thereof.

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine,or a pharmaceutically acceptable salt thereof,2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine,or a pharmaceutically acceptable salt thereof; and further(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4pyrazolyl)carbamoyl]pyrimidine,or a pharmaceutically acceptable salt thereof.

When the compound (I) of the present invention or a pharmaceuticallyacceptable salt thereof has an asymmetric carbon atom at Ring A, R¹and/or R², it may exist in the form of an optically active isomerthereof owing to said asymmetric carbon atom thereof, and the presentinvention also includes these optical isomers and a mixture thereof.

The compound (I) of the present invention or a pharmaceuticallyacceptable salt thereof exhibits an excellent selective PDE V inhibitoryactivity but substantially shows few side effects such as color sensedisorder, and hence, it can be used in the prophylaxis or treatment ofpenile erectile dysfunction.

The present compound (I) can clinically be used either in the free formor in the form of a pharmaceutically acceptable salt thereof. Thepharmaceutically acceptable salt of the compound (I) includes a saltwith an inorganic acid such as hydrochloride, sulfate, nitrate orhydrobromide, or a salt with an organic acid such as acetate, fumarate,oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, ormaleate.

The present compound (I) or a salt thereof includes eitherintramolecular salt or an additive thereof, and solvates or hydratesthereof.

The present compound (I) or a pharmaceutically acceptable salt thereofcan be administered either orally or parenterally, and can be formulatedinto a conventional pharmaceutical preparation such as tablets,granules, fine granules, pills, capsules, powders, injections,inhalants, buccal preparation, sublingual tablets, syrups, dry syrups,jellys, suppositories, ointments, elixirs, liniments, lotions, drinks,nasal drops, percutaneous preparations, and rapidly-disintegratingtablets in oral cavity, etc. These pharmaceutical preparations may beprepared by formulating with a pharmaceutically acceptable additive suchas excipient, binder, wetting agent, disintegrator, thickening agent,etc., by a conventional method.

The dose of the compound (I) of the present invention or apharmaceutically acceptable salt thereof may vary in accordance with theadministration routes, and the ages, weights and conditions of thepatients. For example, when administered in an injection preparation, itis usually in the range of about 0.001-100 mg/kg/day, preferably in therange of about 0.1-10 mg/kg/day. When administered in an oralpreparation, it is usually in the range of about 0.1-200 mg/kg/day,preferably in the range of about 0.1-80 mg/kg/day.

Concomitantly, since the compound (I) of the present invention or apharmaceutically acceptable salt thereof exhibits an excellent selectivePDE V inhibitory activity, it also may be useful in the prophylaxis ortreatment of diseases caused by a functional disorder of cGMP-signaling,such as pulmonary hypertension, diabetic gastroparesis, hypertension,angina pectoris, myocardial infarction, chronic or acute heart failure,female sexual dysfunction, prostatic hyperplasia, asthma, diarrhea,constipation and achalasia in addition to the above-mentioned erectriledysfunction.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds (I) of the present invention may be prepared by thefollowing Processes A to F.

Process A

Among the compounds (I) of the present invention, the compound of theformula (I) wherein R¹ is a group of the formula: —NH—Q—R³ or —NH—R⁴,i.e., the compound of the formula (I-a):

 (wherein R¹¹ is a group of the formula: —NH—Q—R³ or —NH—R⁴, and theother symbols are as defined above) can be prepared by

reacting a compound of the formula (II):

 wherein X¹ is a halogen atom, R⁵ is a protecting group for carboxylgroup, R⁹ is substituted or unsubstituted lower alkyl group or asubstituted or unsubstituted aryl group, and the other symbols are asdefined above,

 with a compound of the formula (III):

R²—CH₂—NH₂  (III)

 wherein the symbols are as defined above,

oxidizing the resulting compound of the formula (IV):

 wherein the symbols are as defined above,

 to give a sulfonyl (or sulfinyl) compound of the formula (V):

 wherein n is 1 or 2, and the other symbols are as defined above,

reacting the compound (V) with a compound of the formula (VI):

 wherein the symbol is as defined above, or a salt thereof, to give acompound of the formula (VII):

 wherein the symbols are as defined above,

removing a protecting group R⁵ for a carboxyl group of the compound(VII) to give a compound of the formula (VIII):

 wherein the symbols are as defined above, and

followed by reacting the compound (VIII) with a compound of the formula(IX-a):

R¹¹—H   (IX-a)

 wherein the symbols are as defined above.

The compound (I-a) can also be prepared by subjecting the compound(VIII) to halogenation to give a compound of the formula (X):

wherein X² is a halogen atom, and the other symbols are as definedabove, and followed by reacting the compound (X) with the compound(IX-a).

In addition, the above compound (VII) can also be prepared by

treating a dihalogeno compound of the formula (XI):

 wherein X³ and X⁴ are a halogen atom, and the other symbols are asdefined above,

 with carbon dioxide,

protecting the carboxyl group of the resulting compound of the formula(XII):

 wherein the symbols are as defined above,

to give a compound of the formula (XIII):

 wherein the symbols are as defined above,

reacting the compound (XIII) with the compound (III) to give a compoundof the formula (XIV):

 wherein the symbols are as defined above, and

followed by reacting the compound (XIV) with the compound (VI).

Further, the above compound (XIV) can also be prepared by subjecting thecompound (V) to hydrolysis, followed by halogenating the resultingcompound of the formula (XV):

wherein the symbols are as defined above.

Process B

Among the compounds (I) of the present invention, the compound of theformula (I) wherein R¹ is a substituted or unsubstituted lower alkylgroup, i.e., the compound of the formula (I-b):

 (wherein R¹² is a substituted or unsubstituted lower alkyl group, andthe other symbols are as defined above) can be prepared by

oxidizing a compound of the formula (XVI):

 wherein the symbols are as defined above, which is obtained byreduction of the compound (IV), to give a compound of the formula(XVII):

 wherein the symbols are as defined above,

further oxidizing the compound (XVII) to give a compound of the formula(XVIII):

 wherein the symbols are as defined above,

reacting the compound (XVIII) with the compound (VI) to give a compoundof the formula (XIX):

 wherein the symbols are as defined above,

reacting the compound (XIX) with a metal salt of a compound of theformula (IX-b):

R¹²—H   (IX-b)

 wherein R¹² is as defined above, to give a compound of the formula(XX):

 wherein the symbols are as defined above,

followed by oxidizing the compound (XX).

In addition, among the compounds (I) of the present invention, thecompound of the formula (I) wherein a group R¹ is a loweralkoxy-substituted ethyl group, a morpholino-substituted ethyl group, a4-lower alkylpiperazinyl group-substituted ethyl group, a3-pyridylamino-substituted ethyl group, a 2-pyridyl-lower alkylaminogroup-substituted ethyl group, a di-lower alkylaminoethyl group or ahydroxyethyl group, i.e., the compound of the formula (I-c):

wherein R⁶ is a lower alkoxy group, a morpholino group, a 4-loweralkylpiperazinyl group, a 3-pyridylamino group, a 2-pyrimidyl-loweralkylamino group, a di-lower alkylamino group or a hydroxy group, andthe other symbols are as defined above,

can be prepared by reacting the compound (XIX) with a Grignard compoundof the formula:

CH₂═CHMgBr   (XXI)

 to give a compound of the formula (XXII):

 wherein the symbols are as defined above,

oxidizing the compound (XXII) to give a compound of the formula (XXIII):

 wherein the symbols are as defined above,

followed by reacting the compound (XXIII) with a compound of the formula(XXIV):

R⁶—H   (XXIV)

 wherein R⁶ is as defined above.

Process C

The compound (I-a) can be prepared by

reacting a compound of the formula (XXV):

 wherein the symbols are as defined above, which is obtained by removingthe protecting group R⁵ for a carboxyl group of the compound (IV), withthe compound (IX-a) to give a compound of the formula (XXVI-a):

 wherein the symbols are as defined above,

oxidizing the compound (XXVI-a) to give a compound of the formula(XXVII-a):

 wherein the symbols are as defined above,

followed by reacting the compound (XXVII-a) with the compound (VI).

Process D

The compound (I-b) can be prepared by

oxidizing a compound of the formula (XXVIII):

 wherein the symbols are as defined above, which is obtained by reactingthe compound (XVII) with a metal salt of the compound (IX-b), to give acompound of the formula (XXVI-b):

 wherein the symbols are as defined above,

further oxidizing the compound (XXVI-b) to give a compound of theformula (XXVII-b):

 wherein the symbols are as defined above,

followed by reacting the compound (XXVII-b) with the compound (VI).

Process E

The compound (I-b) can be prepared by

oxidizing a compound of the formula (XXX):

 wherein the symbols are as defined above, which is obtained by reactingthe dihalogeno compound (XI) with a compound of the formula (XXIX):

R¹²—CHO   (XXIX)

 wherein R¹² is as defined above, to give a compound of the formula(XXXI):

 wherein the symbols are as defined above,

reacting the compound (XXXI) with the compound (III) to give a compoundof the formula (XXXII):

 wherein the symbols are as defined above,

followed by reacting the compound (XXXII) with the compound (VI).

The above compound (XXXII) can also be prepared by reacting the compound(XXX) with the compound (III) to give a compound of the formula(XXXIII):

 wherein the symbols are as defined above,

followed by oxidizing the compound (XXXIII).

Process F

The compound (I-a) can be prepared by

reacting the compound (XIII) with a compound of the formula (XXXIV):

RSH   (XXXIV)

 wherein R is a substituted or unsubstituted lower alkyl group or asubstituted or unsubstituted aryl group, to give a compound of theformula (XXXV):

 wherein the symbols are as defined above,

reacting the compound (XXXV) with the compound (VI) or a salt thereof togive a compound of the formula (XXXVI):

 wherein the symbols are as defined above,

removing the protecting group R⁵ for a carboxyl group of the compound(XXXVI) to give a compound of the formula (XXXVII):

 wherein the symbols are as defined above,

reacting the compound (XXXVII) with the compound (IX-a) to give acompound of the formula (XXXIX):

 wherein the symbols are as defined above,

subjecting the compound (XXXIX) to oxidation to give a sulfonyl orsulfinyl compound,

followed by reacting the resultant with the compound (III).

The above Processes A to F can be carried out as follows.

Process A

The reaction of the compound (II) with the compound (III) is carried outin the presence or absence of an acid scavenger in a solvent. The acidscavenger includes, for example, an organic base such asN,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine,etc., and an inorganic base such as sodium hydride, sodium carbonate,potassium carbonate, sodium hydrogen carbonate, etc. The solvent may beany solvents which do not disturb the reaction, for example,dimethylsulfoxide, tetrahydrofuran, toluene, ethyl acetate, chloroform,dimethoxyethane, xylene, N,N-dimethylformamide, etc. The reaction iscarried out at a temperature of from −10° C. to room temperature,preferably at a temperature of from 0° C. to room temperature.

The reaction of oxidizing the compound (IV) to give the sulfonyl (orsulfinyl) compound (V) is carried out in the presence of an oxidizingagent in a solvent. The oxidizing agent includes, for example, peracidssuch as m-chloroperbenzoic acid, peracetic acid, etc., and an inorganicoxidizing agent such as manganese dioxide, sodium periodate, hydrogenperoxide, dinitrogen tetroxide, halogen, hydroperoxide, iodobenzeneacetate, t-butyl hypochlorite, sulfuryl chloride, potassiumperoxymonosulfate, etc. The solvent may be any solvent which does notdisturb the reaction, for example, chloroform, methylene chloride,dichloroethane, acetic acid, etc. The reaction is carried out at atemperature of from −78° C. to 50° C., preferably at a temperature offrom −10° C. to 10° C.

The reaction of the compound (V) with the compound (VI) or a saltthereof can be carried out in the presence or absence of an acidscavenger in a solvent. The acid scavenger includes, for example, anorganic base such as N,N-diisopropylethylamine, N-methylmorpholine,triethylamine, pyridine, etc., and an inorganic base such as sodiumhydride, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc. The salt of the compound (VI) is preferably an alkalimetal salt such as sodium salt, potassium salt, etc. The solvent may beany solvent which does not disturb the reaction, for example,N,N-dimethylformamide, tetrahydrofuran, dimethoxyethane,dimethylsulfoxide, etc. The reaction is carried out at a temperature offrom 0° C. to 150° C., preferably at a temperature of from roomtemperature to 60° C.

The reaction of removing the protecting group R⁵ for a carboxyl group ofthe compound (VII) to give the compound (VIII) can be carried out by aconventional method such as hydrolysis, catalytic reduction, etc. whichis selected according to the types of the protecting group for acarboxyl group to be removed. When a protecting group for a carboxylgroup is removed by hydrolysis, the hydrolysis is carried out, forexample, in the presence of a base in a solvent. The base is preferably,for example, an alkali metal hydroxide such as sodium hydroxide,potassium hydroxide, lithium hydroxide, etc., or an alkali metalcarbonate such as sodium carbonate, potassium carbonate, etc. Thesolvent may be water or a mixture of water and methanol, ethanol,tetrahydrofuran, dioxane, N,N-dimethyformamide, dimethylsulfoxide, etc.The reaction is carried out at a temperature of from 0 to 80° C.,preferably at a temperature of from 5° C. to 60° C. The protecting groupfor a carboxyl group represented by R⁵ may be any conventionalprotecting group for a carboxyl group, such as a lower alkyl group,benzyl group, etc.

The reaction of the compound (VIII) with the compound (IX-a) can becarried out in the presence or absence of a condensing agent, a base oran activating agent in a suitable solvent. The condensing agentincludes, for example, dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, diphenylphosphorylazide, diethylcyano-phosphonate, etc., which is usually used in thepeptide synthesis. The base includes, for example, an organic base suchas triethylamine, N-methymorpholine, etc., and the activating agentincludes, for example, 1-hydroxybenzotriazole, etc. The solvent may beany solvent which does not disturb the reaction, for example, methylenechloride, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,N,N-dimethylacetamide, ethyl acetate, etc. The reaction is carried outat a temperature of from −30° C. to 50° C., preferably at a temperatureof from −10° C. to 10° C.

The alternative process of converting the compound (VIII) into thecompound (X), which is further reacted with the compound (IX-a) can becarried out by firstly reacting the compound (VIII) with a halogenatingagent in the presence or absence of an activating agent by aconventional method, and reacting the resulting compound (X) with thecompound (IX-a). The reaction of the compound (VIII) with a halogenatingagent is carried out in a solvent. The halogenating agent is preferablythionyl chloride, oxalyl chloride, phosphorus pentachloride, etc. Theactivating agent is preferably an amide compound such asN,N-dimethylformamide, etc. The solvent may be any solvent which doesnot disturb the reaction, for example, methylene chloride, chloroform,tetrahydrofuran, benzene,(toluene, dioxane, etc. The reaction is carriedout at a temperature of from −30° C. to 100° C., preferably at atemperature of from −5° C. to 10° C.

The subsequent reaction with the compound (IX-a) is carried out in thepresence of an acid scavenger in a solvent. The acid scavenger includes,for example, an organic base such as N,N-diisopropylethylamine,N-methylmorpholine, triethylamine, pyridine, dimethylaminopyridine,etc., and an inorganic base such as sodium hydride, sodium carbonate,potassium carbonate, sodium hydrogen carbonate, etc. The solvent may beany solvent which does not disturb the reaction, for example,tetrahydrofuran, methylene chloride, chloroform, toluene, benzene,dioxane, ethyl acetate, etc. The reaction is carried out at atemperature of from −30° C. to 100° C., preferably at a temperature offrom −5° C. to 10° C.

The reaction of treating the dihalogeno compound (XI) with carbondioxide to give the compound (XII) can be carried out in the presence ofa base in a solvent. The base includes, for example, an alkali metalsalt of an organic base such as lithium diisopropylamide, lithium2,2,6,6-tetramethylpiperidide, etc. The solvent may be any solvent whichdoes not disturb the reaction, for example, tetrahydrofuran,1,2-dimethoxyethane, diethyl ether, etc. The reaction is carried out ata temperature of from −100° C. to −30° C., preferably at a temperatureof from −100° C. to −70° C.

The reaction of protecting the carboxyl group of the compound (XII) togive the compound (XIII) can be carried out by a conventional method,for example, by reacting with an alkylating agent in the presence of abase in a solvent, when the protecting group is a lower alkyl group. Thealkylating agent is preferably a lower alkyl halide such as methyliodide. The base is preferably an alkali metal hydrogen carbonate suchas sodium hydrogen carbonate, and the solvent may be any solvent whichdoes not disturb the reaction, for example, N,N-dimethylformamide,tetrahydrofuran, etc. The reaction is carried out at a temperature offrom 0° C. to 100° C., preferably at a temperature of from roomtemperature to 70° C.

The reaction of the compound (XIII) with the compound (III) to give thecompound (XIV) can be carried out in the same manner as in the reactionof the compound (II) with the compound (III).

The reaction of the compound (XIV) with the compound (VI) to give thecompound (VII) can be carried out in the same manner as in the reactionof the compound (V) with the compound (VI).

The hydrolysis reaction of the compound (V) to give the compound (XV)can be carried out in the presence of a base in a solvent. The baseincludes, for example, an alkali metal hydroxide such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, etc., and an alkalimetal carbonate such as sodium carbonate, potassium carbonate, etc. Thesolvent is preferably water, or a mixture of water and methanol,ethanol, tetrahydrofuran, dioxane, N,N-dimethylformamide,dimethylsulfoxide, etc. The reaction is carried out at a temperature offrom −20° C. to 80° C., preferably at a temperature of from −5° C. to60° C.

The reaction of halogenating the compound (XV) to give the compound(XIV) can be carried out in the same manner as in the reaction ofobtaining the compound (X) by halogenating the compound (XIII) by ahalogenating agent.

Process B

The reduction reaction of the compound (IV) to give the compound (XVI)can be carried out in the presence of a reducing agent in a suitablesolvent. The reducing agent is preferably an alkali metal aluminumhydride such as lithium aluminum hydride, and an alkali metalborohydride such as lithium borohydride, etc. The solvent may be anysolvent which does not disturb the reaction, for example,tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, etc. Thereaction is carried out at a temperature of from −78° C. to a boilingpoint of the solvent to be used, preferably at a temperature of from−10° C. to room temperature.

The oxidation reaction of the compound (XVI) to give the compound (XVII)can be carried out in the presence of an oxidizing agent in a solvent.The oxidizing agent may be any one which can convert an alcohol into acarbonyl compound, for example, manganese dioxide, barium permanganate,potassium permanganate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,pyridinium chlorochromate, pyridinium dichloromate, etc. The solvent maybe any solvent which does not disturb the reaction, for example,chloroform, toluene, ethyl acetate, 1,2-dichloroethane, methylenechloride, tetrahydrofuran, etc. The reaction is carried out at atemperature of from 0° C. to 100° C., preferably at a temperature offrom room temperature to 70° C.

The oxidation reaction of the compound (XVII) to give the compound(XVIII) is carried out in the same manner as in the reaction ofobtaining the compound (V) by oxidizing the compound (IV).

The reaction of the compound (XVIII) with the compound (VI) to give thecompound (XIX) is carried out in the same manner as in the reaction ofthe compound (V) with the compound (IV).

The reaction of the compound (XIX) with a metal salt of the compound(IX-b) to give the compound (XX) may be carried out in a suitablesolvent. The metal salt of the compound (IX-b) is preferably lithiumsalt, etc. The solvent may be any solvent which does not disturb thereaction, for example, tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane, etc. The reaction may preferably proceed at atemperature of from −78° C. to room temperature.

The oxidation reaction of the compound (XX) to give the compound (I-b)may be carried out in the same manner as in the reaction of obtaining(XVII) by oxidizing the compound (XVI).

The reaction of the compound (XIX) with the Grignard compound can becarried out in a suitable solvent. The solvent is preferablytetrahydrofuran, dioxane, diethyl ether, etc. The reaction maypreferably proceed at a temperature of from −78° C. to 60° C.,preferably at a temperature of from −78° C. to room temperature.

The oxidation reaction of the compound (XXII) to give the compound(XXIII) is carried out in the same manner as in the reaction ofobtaining the compound (XVII) by oxidizing the compound (XVI).

The reaction of the compound (XXIII) with the compound (XXIV) wherein R⁶is a morpholino group, a 4-lower alkylpiperazinyl group, a3-pyridylamino group, a 2-pyrimidyl-lower alkylamino group, or adi-lower alkylamino group to give the compound (I-c) wherein R⁶ is amorpholino group, a 4-lower alkylpiperazinyl group, a 3-pyridylaminogroup, a 2-pyrimidinyl-lower alkylamino group, or a di-lower alkylaminogroup can be carried out in the presence or absence of a base in asuitable solvent. The base includes, for example, an organic base suchas N,N-diisopropylethylamine, N-methylmorpholine, triethylamine,pyridine, etc., and an inorganic base such as sodium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, etc. Thesolvent may preferably be ethanol, N,N-dimethylformamide,tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, etc. The reactionmay preferably proceed at a temperature of from 0° C. to 150° C.,preferably at a temperature of from room temperature to 60° C.

On the other hand, the reaction of the compound (XXIII) with thecompound (XXIV) wherein R⁶ is a hydroxy group or a lower alkoxy group togive the compound (XXI) wherein R⁶ is a hydroxy group or a lower alkoxygroup can be carried in the presence of an acid in a solvent or withouta solvent. The acid includes, for example, an inorganic acid such assulfuric acid, etc., or an organic acid such as methanesulfonic acid,camphorsulfonic acid, toluenesulfonic acid, benzenesulfonic acid, etc.The solvent may preferably be diethyl ether, toluene, benzene,N,N-dimethylformamide, dimethoxyethane, dimethylsulfoxide, etc. Thereaction may preferably proceed at a temperature of from 0° C. to 150°C., preferably at a temperature of from room temperature to 60° C.

Process C

The reaction of removing the protecting group R⁵ for a carboxyl group ofthe compound (IV) to give the compound (XXV) can be carried out in thesame manner as in the reaction of obtaining the compound (VIII) byremoving the protecting group R⁵ for a carboxyl group of the compound(VII).

The reaction of the compound (XXV) with the compound (IX-a) to give thecompound (XXVI-a) can be carried out in the same manner as in thereaction of the compound (VIII) with the compound (IX-a).

The reaction of oxidizing the compound (XXVI-a) to give the compound(XXVII-1) can be carried out in the same manner as in the reaction ofobtaining the compound (V) by oxidizing the above compound (IV).

The reaction of the compound (XXVII-a) with the compound (VI) to givethe compound (I-a) of the present invention can be carried out in thesame manner as in the reaction of the compound (V) with the compound(VI).

Process D

The reaction of the compound (XVII) with a metal salt of the compound(IX-b) to give the compound (XXVIII) can be carried out in the samemanner as in the reaction of the compound (XIX) with a metal salt of thecompound (IX-b).

The reaction of oxidizing the compound (XXVIII) to give the compound(XXVI-b) can be carried out in the same manner as in the reaction ofobtaining the compound (XVII) by oxidizing the compound (XVI).

The process wherein the compound (XXVI-b) is oxidized to give thecompound (XXVII-b) which is further converted into the compound (I-b) ofthe present invention can be carried out in the same manner as in theprocess wherein the compound (XXVI-a) is oxidized to give the compound(XXVII-a) which is further converted into the compound (I-a) of thepresent invention.

Process E

The reaction of the compound (XI) with the compound (XXIX) to give thecompound (XXX) is carried out in the presence of a base in a suitablesolvent. The base includes, for example, an alkali metal salt of anorganic base such as lithium diisopropylamide, lithium2,2,6,6-tetramethylpiperidide, etc. The solvent may be any solvent whichdoes not disturb the reaction, for example, tetrahydrofuran,1,2-dimethoxyethane, diethyl ether, etc. The reaction is carried out ata temperature of from −100° C. to −30° C., preferably at a temperatureof from −100° C. to −70° C.

The reaction of oxidizing the compound (XXX) to give the compound (XXXI)can be carried out in the same manner as in the reaction of oxidizingthe compound (XVI) to give the compound (XVII).

The reaction of the compound (XXXI) with the compound (III) to give thecompound (XXXII) can be carried out in the same manner as in thereaction of the compound (II) with the compound (III).

The reaction of the compound (XXXII) with the compound (VI) or a saltthereof to give the compound (I-b) of the present invention can becarried out in the same manner as in the reaction of the compound (V)with the compound (VI).

The reaction of the compound (XXX) with the compound (III) to give thecompound (XXXIII) can be carried out in the same manner as in thereaction of the compound (II) with the compound (III). Besides, thereaction of oxidizing the compound (XXXIII) to give the compound (XXXII)can be carried out in the same manner as in the reaction of oxidizingthe compound (XVI) to give the compound (XVII).

Process F

The reaction of the compound (XIII) with the compound (XXXIV) can becarried out in the presence or absence of an acid scavenger in asolvent. The acid scavenger includes, for example, an organic base suchas N,N-diisopropylethylamine, N-methylmorpholine, triethylamine,pyridine, etc., or an inorganic base such as sodium hydride, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, etc. Thesolvent may be any solvent which does not disturb the reaction, forexample, N,N-dimethylformamide, tetrahydrofuran, toluene, ethyl acetate,chloroform, dimethoxyethane, xylene, dimethylformamide, etc. Thereaction is carried out at a temperature of from −10° C. to roomtemperature, preferably at a temperature of from 0° C. to roomtemperature.

The reaction of the compound (XXXV) with the compound (VI) or a saltthereof can be carried out in the same manner as in the reaction of thecompound (V) with the compound (VI).

The reaction of removing the protecting group R⁵ for a carboxyl group ofthe compound (XXXVI) to give the compound (XXXVII) can be carried out inthe same manner as in the reaction of removing the protecting group R⁵for a carboxyl group of the compound (VII) to give the compound (VIII).

The reaction of the compound (XXXVII) with the compound (IX-a) can becarried out in the same manner as in the reaction of the compound (VIII)with the compound (IX-a).

The oxidation reaction of the compound (XXXIX) can be carried out in thesame manner as the reaction of the compound (IV) to give the compound(V). The oxidating agent is preferably m-chloroperbenzoic acid, etc. Thesolvent may be any solvent which does not disturb the reaction, forexample, chloroform, methylene chloride, dichloroethane, acetic acid,etc. The reaction is carried out at a temperature of from −78° C. to 50°C., preferably at a temperature of from −10° C. to 10° C.

The subsequent reaction with the compound (III) can be carried out inthe same manner as in the reaction of the compound (II) and the compound(III).

The compound (I) thus obtained can be converted into a pharmaceuticallyacceptable salt thereof.

The starting compound (II) can be prepared, for example, according tothe method disclosed in Journal of American Chemical Society, p. 350,vol. 65, 1943.

Examples of the compound (I) of the present invention which can beprepared by the above exemplified methods are illustrated below, but thepresent invention should not be construed to be limited thereto.

EXAMPLE 1

(1) To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthio-pyrimidine(25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethyl-formamide (15ml) and triethylamine (16.7 ml) under ice-cooling. The mixture isstirred at room temperature for 20 minutes, and thereto is added3-chloro-4-methoxybenzylamine (940 mg), and the mixture is furtherstirred for 15 minutes. To the mixture is further added said amine (940mg), and the mixture is stirred for 15 minutes. The reaction mixture ispoured into a mixture of ice water and citric acid, and the mixture isextracted with ethyl acetate. The extract is washed successively with a10% aqueous citric acid solution, water and brine, and dried overanhydrous sodium sulfate. The solvent is evaporated under reducedpressure, and the residue is washed with n-hexane to give4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine(38.34 g), m.p. 86° C.

(2) To a solution of the compound (5.00 g) obtained in the above (1) inchloroform (50 ml) is added a solution of m-chloroperbenzoic acid (4.00g) in chloroform (50 ml) under ice-cooling, and the mixture is stirredfor 2 hours. The reaction mixture is washed with a saturated aqueoussodium hydrogen carbonate solution and brine, and the organic layer isdried over anhydrous sodium sulfate, and the solvent is evaporated underreduced pressure to give crude4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylsulfinylpyrimidine,MS (m/z): 447 (MH⁺).

(3) The crude product obtained in the above (2) is dissolved intetrahydrofuran (40 ml), and thereto is added a solution of L-prolinol(1.50 g) and triethylamine (1.60 g) in tetrahydrofuran (10 ml) at roomtemperature. The mixture is stirred overnight, and the reaction mixtureis diluted with ethyl acetate, and washed with aqueous sodium hydrogencarbonate solution and brine. The organic layer is dried over anhydroussodium sulfate, and the solvent is evaporated under reduced pressure.The residue is purified by silica gel column chromatography (solvent;chloroform) and crystallized from a mixture of ether and n-hexane togive(S)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxy-carbonyl-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine(4.72 g), m.p. 88-90° C., MS (m/z): 421 (MH⁺).

(4) A mixture of the compound (3.4 g) obtained in the above (3), a 10%aqueous sodium hydroxide solution (23 ml), and dimethylsulfoxide (34 ml)is stirred at room temperature for 15 hours. The reaction mixture ispoured into a 10% aqueous citric acid solution, and the precipitates arecrystallized from a mixture of tetrahydrofuran and ether to give(S)-4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine(2.52 g), m.p. 205-208° C. MS (m/z): 391 (M−H)⁻.

(5) A mixture of the compound (600 mg) obtained in the above (4),2-aminomethylpyrimidine (217 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (323 mg),1-hydroxybenzotriazole monohydrate (227 mg) and N,N-dimethylformamide(12 ml) is stirred at room temperature for 8 hours, and the reactionmixture is poured into aqueous sodium hydrogen carbonate solution. Themixture is extracted with ethyl acetate, washed with brine, and driedover anhydrous sodium sulfate. The solvent is evaporated under reducedpressure, and the residue is purified by silica gel columnchromatography (solvent; chloroform:methanol=50:1) to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidine(610 mg), m.p. 160-163° C.

EXAMPLE 2

(1) To a suspension of lithium aluminum hydride (4.15 g) intetrahydrofuran (150 ml) is added a solution of2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(38.32 g) in tetrahydrofuran (100 ml) under ice-cooling at 5° C. to 10°C. over a period of one hour. After the addition, the ice bath isremoved, and the reaction mixture is stirred at room temperature for onehour. To the reaction mixture is added water (4.15 ml) underice-cooling, and thereto is further added 3N aqueous sodium hydroxidesolution (4.15 ml). To the mixture is added water (4.15 ml) three times,and the mixture is stirred at room temperature for one hour. Thereaction mixture is treated with magnesium sulfate, and the solidprecipitates obtained are filtered. The precipitates are washed withtetrahydrofuran. The filtrate and the washings are combined, andconcentrated under reduced pressure, and triturated with a mixture ofethyl acetate and isopropyl ether. The resulting crystals are collectedby filtration, and washed well with isopropyl ether to give2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidineas a pale yellow crystalline powder.

First production: yield; 25.10 g, m.p. 162-163° C.

Second production: yield; 2.32 g, m.p. 159-160° C.

In addition, the above solid precipitates are washed again withisopropyl ether, and the filtrate is concentrated under reduced pressureto give colorless crystals. The resulting solid is suspended inisopropyl ether, filtered, and the precipitates are washed well withisopropyl ether and hexane to give2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine(4.26 g) as colorless crystals, m.p. 161-162° C.

(2) To a suspension of2-methylthio-4-(3-chloro-4-methoxybenzyl-amino)-5-hydroxymethylpyrimidine(25.10 g) obtained in the above (1) in chloroform (150 ml) is addedmanganese dioxide powder (37.6 g), and the mixture is vigorously stirredat room temperature for one day. To the mixture is further addedmanganese dioxide powder (12.6 g, 0.5 time amount of the startingcompound), and the mixture is stirred for three days. The insolublematerials are quickly removed by filtration on celite, and the filtrateis concentrated under reduced pressure. The residue is suspended in amixture of ethyl acetate and isopropyl ether. The precipitates arefiltered, and washed successively with isopropyl ether and hexane togive 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine(22.43) as colorless crystals, m.p. 124-125° C.

(3) A solution of2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (2.057g) in chloroform (20 ml) is treated with m-chloroperbenzoic acid (80%,1.468 g) at 0° C. for 30 minutes. To the reaction mixture are is addedL-prolinol (0.901 g), and then triethylamine (1.33 ml), and the mixtureis reacted at 0° C. for one hour. The reaction mixture is warmed to roomtemperature, and diluted with ethyl acetate. The mixture is washedsuccessively with a saturated aqueous sodium hydrogen carbonatesolution, water and a saturated sodium chloride solution, and dried overanhydrous sodium sulfate. The precipitates are removed by filtrationthrough a silica plug. The filtrate is concentrated under reducedpressure to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (1.9990 g) as colorless amorphous, MS (m/z): 377(MH⁺).

(4) To a solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine(91.0 mg) in tetrahydrofuran (20 ml) is added 1.10 M solution of methyllithium in ether (1.1 ml) at −78° C., and the mixture is reacted for 10minutes, and thereto is added aqueous sodium hydrogen carbonatesolution. The reaction mixture is extracted with ethyl acetate to givecrude(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxyethyl)pyrimidine,MS (m/z): 393 (MH³⁰).

(5) The crude product obtained in the above (4) is treated withmanganese dioxide (0.5 g) at room temperature, and the mixture isstirred overnight. The reaction mixture is heated under reflux for 5hours, and the insoluble materials are removed by filtration. Thefiltrate is concentrated under reduced pressure, and purified by silicagel column chromatography (solvent; chloroform:ethyl acetate=3:1) togive (S) -(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-acetylpyrimidine (56.7 mg) ascolorless oil, MS (m/z): 391 (MH⁺).

EXAMPLE 3

(1) To a solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine(84 mg) in tetrahydrofuran (about 1 ml) is added dropwise a 1.0Msolution of vinyl magnesium bromide in tetrahydrofuran in a dryice-acetone bath. The reaction mixture is stirred at −78° C. for 10minutes, and stirred at room temperature for 10 minutes. The reactionmixture is poured into a mixture of ice and a saturated aqueous sodiumhydrogen carbonate solution, and the mixture is extracted with ethylacetate. The organic layer is washed successively with water and brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure.

The obtained crude product is subjected to preparative thin layerchromatography (solvent; ethyl acetate:methanol=20:1) to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxy-2-propen-1-yl)pyrimidine(30 mg) as colorless oil, MS (m/z): 405 (MH⁺).

(2) To a solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxy-2-propen-1-yl)pyrimidine(144 mg) in chloroform (2.5 ml) is added manganese dioxide (432 mg), andthe mixture is vigorously stirred at room temperature for three days.The insoluble materials are removed by filtration on celite, and thefiltrate is concentrated under reduced pressure to give pale yellow oil(124 mg). The resulting crude product is purified by silica gel columnchromatography (silica gel 20 g, solvent; chloroform:ethyl acetate=2:1)to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-acryloyl)pyrimidine(90 mg) as colorless crystals, m.p. 113-115° C., MS (m/z): 403 (MH⁺).

(3) To a solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(acryloyl)pyrimidine(72 mg) in ethanol (2 ml) is added morpholine (78 μl) at roomtemperature, and the mixture is stirred at room temperature for 40minutes. The reaction mixture is concentrated under reduced pressure,and the residue is poured into water, and the mixture is extracted withethyl acetate. The organic layer is washed successively with water andbrine, dried over anhydrous magnesium sulfate, and concentrated todryness under reduced pressure to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-morpholinoethyl)carbonyl]-pyrimidine(91 mg).

The obtained crude product is dissolved in ethyl acetate (10 ml), andthe solution is treated with a saturated solution of hydrochloric acidin methanol (5 ml), and concentrated under reduced pressure. To theresidue is added ethyl acetate, and the mixture is filtered. Theresulting solid is washed well with hexane to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-morpholinoethyl)carbonyl]pyrimidinedihydrochloride (65 mg), MS (m/z): 490 (MH⁺).

EXAMPLE 4

(1) To a solution of4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine(972 mg) obtained in the above Example 1-(1) in chloroform (8 ml) isadded a solution of m-chloroperbenzoic acid (80%, 598 mg) in chloroform(10 ml) under ice-cooling over a period of 30 minutes. The reactionmixture is stirred under ice-cooling for one hour. The reaction mixtureis diluted with a saturated aqueous sodium hydrogen carbonate solution,and the chloroform layer is collected, washed successively with asaturated aqueous sodium hydrogen carbonate solution, water and asaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to quantitatively give2-methylsulfinyl-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-pyrimidineas colorless caramels, MS (m/z): 384 (MH⁺).

(2) To a solution of2-methylsulfinyl-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(whole amount) obtained in the above (1) in tetrahydrofuran (6 ml) isadded dropwise a 2N aqueous sodium hydroxide solution (1.32 ml) underice-cooling over a period of 2 minutes. The reaction mixture is stirredunder ice-cooling for 30 minutes, and thereto are added tetrahydrofuran(8 ml) and N,N-dimethylacetamide (6 ml). The reaction mixture is stirredunder ice-cooling for 30 minutes, and thereto are added water (5 ml) andN,N-dimethylacetamide (2 ml), and stirred under ice-cooling for onehour. The reaction mixture is acidified with a 10% aqueous citric acidsolution, diluted with water, and extracted twice with ethyl acetate.The extracts are combined, washed with water and a saturated aqueoussodium chloride solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is separated by silicagel column chromatography (silica gel: 20 g, solvent; chloroform: ethylacetate=5:1→chloroform:isopropanol=30:1) to give2-hydroxy-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(618 mg) as slightly yellow crystalline powder, m.p. 195-197° C.

(3) A mixture of2-hydroxy-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(500 mg) obtained in the above (2), diethylaminobenzene (2 ml) andphosphorus oxychloride (4 ml) is stirred at 80° C. for 30 minutes, andstirred at 100° C. for 5 hours. After cooling, the reaction solution ispoured into ice-water, and the mixture is stirred at room temperaturefor 30 minutes. The resulting mixture is extracted with ethyl acetate,and the organic layer is washed with water and a saturated aqueoussodium chloride solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (silica gel: 7 g, solvent; chloroform) to give2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(375 crystalline powder, m.p. 114-115°, MS (m/z): 356 (MH⁺).

(4) A mixture of2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(285 mg) obtained in the above (3),5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (197 mg), triethylamine (0.22ml) and chloroform (3 ml) is stirred at room temperature for 2.5 hours,and stirred at 60° C. for 2.5 hours. The reaction mixture is dilutedwith ethyl acetate, and washed with water. The aqueous layer isextracted with ethyl acetate, and the organic layer is washed with waterand a saturated aqueous sodium chloride solution, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (silica gel: 10 g, solvent;chloroform:methanol=50:1), and concentrated under reduced pressure. Theresultant is triturated with isopropyl ether to give2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(290 mg) as colorless crystalline powder, m.p. 179-182° C., MS (m/z):443 (MH⁺).

(5) A suspension of2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(290 mg) obtained in the above (4) and 2N aqueous sodium hydroxidesolution (1.64 ml) in a mixture of dimethylsulfoxide (5 ml) and water (1ml) is stirred at room temperature for one hour. To the mixture is addedtetrahydrofuran (5 ml), and the mixture is stirred at room temperaturefor 13 hours. Tetrahydrofuran is evaporated under reduced pressure, andthe resulting solution is diluted with water, and neutralized with a 10%aqueous citric acid solution. The precipitates are collected byfiltration, washed with water, methanol and isopropyl ether to give2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine(187 mg) as colorless crystalline powder, m.p. 223-226° C. (decomposed),MS (m/z): 413 (M−H)⁻.

(6) A mixture of2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine(60 mg), 4-methyl-2-aminomethylmorpholine (22.7 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.6 mg),1-hydroxybenzo-triazole (21.6 mg) and N,N-dimethylformamide (3 ml) isstirred at room temperature for 22 hours. Water is poured into thereaction mixture, and the mixture is extracted with ethyl acetate. Theorganic layer is washed successively with water, a saturated aqueoussodium hydrogen carbonate solution, water and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive the colorless crystals (70.0 mg), which are further recrystallizedfrom a mixture of chloroform and hexane to give2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-[(4-methyl-2-morpholinyl)methyl]carbamoyl]pyrimidine(51.7 mg) as colorless needles, m.p. 132-134° C., MS (m/z): 527 (MH⁺).

EXAMPLES 5-6

The corresponding starting materials are treated in a similar manner asin Example 4-(6) to give the compounds as listed in the following Table1.

TABLE 1

Ex. No. R¹ Physiochemical properties 5

Powder MS(m/z): 506 (MH⁺) 6

Powder MS(m/z): 512 (MH⁺)

EXAMPLE 7-21

The corresponding starting materials are treated in a similar manner togive the compounds as listed in the following Table 2.

TABLE 2

Ex. No.

R⁰ R¹ Physiochemical properties 7

Cl

Amorphous MS(m/z): 538(MH⁺) 8

Cl

Amorphous MS(m/z): 526(MH⁺) 9

CN

M.p. 243-245° C. 10

CN

Amorphous MS(m/z): 500(MH⁺) 11

CN

M.p. 129-132° C. 12

Cl

M.p. 150-152° C. 13

Cl

Powder (HCl) MS(m/z): 483(MH⁺) 14

Cl

Amorphous MS(m/z): 484(MH⁺) 15

Cl

Caramel MS(m/z): 505(MH⁺) 16

Cl

Amorphous MS(m/z): 503(MH⁺) 17

Cl

Amorphous MS(m/z): 484(MH⁺) 18

Cl

Amorphous MS(m/z): 484(MH⁺) 19

Cl

Amorphous MS(m/z): 505(MH⁺) 20

Cl

Foam MS(m/z): 503(MH⁺) 21

Cl

Amorphous MS(m/z): 514(MH⁺)

EXAMPLE 22

(1) To a solution of diisopropylamine (0.78 g) in tetrahydrofuran (40ml) is added dropwise a 1.6M solution of n-butyl lithium in hexane (4.82ml) in a dry ice-acetone bath over a period of 3 minutes. The mixture isstirred in the same bath for 30 minutes. To the mixture is addeddropwise a solution of 2,6-dichloropyrazine (0.50 g) in tetrahydrofuran(5 ml) at the same temperature over a period of 15 minutes, and themixture is stirred for one hour. The reaction mixture is poured into dryice, and the mixture is stirred at room temperature for one hour. Thereaction mixture is diluted with a 10% aqueous hydrochloric acidsolution in order to adjust the pH value thereof to about 2, and thenextracted with ethyl acetate. The combined organic layers are extractedwith a saturated aqueous sodium hydrogen carbonate solution, and theaqueous extract is washed with ethyl acetate, acidified with a 10%aqueous hydrochloric acid, and extracted with ethyl acetate. Thecombined organic layer is washed with water and a saturated aqueoussodium chloride solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is triturated with amixture of chloroform and hexane (1:1) to give2-carboxy-3,5-dichloropyrazine (234 mg) as a slightly brown crystallinepowder, m.p. 139-141° C., MS (m/z): 191 (M−H)⁻.

(2) A mixture of 2-carboxy-3,5-dichloropyrazine (226 mg) obtained in theabove (1), sodium hydrogen carbonate (118 mg), methyl iodide (0.5 ml)and N,N-dimethylformamide (1.8 ml) is stirred at room temperature for 14hours. The mixture is diluted with a 10% aqueous citric acid solution,and extracted with ethyl acetate. The combined organic layer is washedwith water and a saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive 2-methoxycarbonyl-3,5-dichloropyrazine (245 mg) as pale browncrystalline powder, m.p. 60-63° C., MS (m/z): 206 (M⁺).

(3) A mixture of 2-methoxycarbonyl-3,5-dichloropyrazine (234 mg)obtained in the above (2), 3-chloro-4-methoxybenzylamine (204 mg),triethylamine (0.17 ml) and dry toluene (3 ml) is stirred at roomtemperature for 7 hours. The reaction mixture is diluted with a 10%aqueous citric acid solution, and extracted with ethyl acetate. Theextract is washed with water and a saturated aqueous sodium chloridesolution, dried over sodium sulfate, and concentrated under reducedpressure. The residue is separated and purified by silica gel columnchromatography (silica gel: 5 g, solvent; hexane:chloroform=1:1), andthe desired fractions are concentrated under reduced pressure to give2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-chloropyrazine(102 mg) as pale yellow crystalline powder, m.p. 149-151° C., MS (m/z):342 (MH⁺).

(4) A mixture of2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-chloropyrazine(150 mg), 2-hydroxymethylpyrrolidine (88.6 mg), and triethylamine (0.12ml) in tetrahydrofuran (5 ml) is stirred at room temperature for 4hours, and the mixture is heated at 50° C. for 2 hours. To the mixtureis added 2-hydroxymethylpyrrolidine (44.3 mg), and the mixture isstirred at 50° C. for one hour. After cooling, water is added to thereaction mixture, and the mixture is extracted with ethyl acetate. Theextract is washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting yellowoil is purified by silica gel column chromatography (solvent;chloroform:hexane=1:1) to give(S)-2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)-pyrazine(123 mg) as pale yellow powder, MS (m/z): 407 (MH⁺).

(5) To a solution of(S)-2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine(775 mg) obtained in the above (4) in ethanol (8 ml) is added a 4Naqueous sodium hydroxide solution (1.43 ml), and the mixture is stirredat room temperature for 24 hours. The reaction mixture is acidified with10% aqueous hydrochloric acid solution, and extracted with ethylacetate. The organic layer is washed with water and brine, dried overanhydrous sodium sulfate, concentrated under reduced pressure, andwashed with diisopropyl alcohol to give(S)-2-carboxy-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine(537 mg) as yellow crystals, m.p. 169-171° C., MS (m/z): 391 (M−H)⁻.

(6) A mixture of(S)-2-carboxy-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine(80 mg) obtained in the above (5), 2-aminomethylpyrimidine (26.7 mg),1,2-dichloroethane (43 mg), 1-hydroxybenzotriazole (30.3 mg) inN,N-dimethylformamide (3 ml) is stirred at room temperature for 18hours. Water is poured into the reaction mixture, and extracted withethyl acetate. The extract is washed with water, a saturated aqueoussodium hydrogen carbonate solution, and brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (solvent; ethyl acetate) togive(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine(87.6 mg), MS (m/z): 484 (MH⁺).

EXAMPLES 23-24

The corresponding starting materials are treated in a similar manner asin Example 22 to give the compounds as listed in the following Table 3.

TABLE 3

Ex. No.

R¹ Physico- chemical properties 23

Amor- phous MS(m/z): 506(MH⁺) 24

Amor- phous MS(m/z): 505(MH⁺)

EXAMPLE 25

A mixture of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(acryloyl)pyrimidine(31 mg), methanol (1 ml) and conc. sulfuric acid (one drop) is heatedunder reflux for 2 days. After the reaction is complete, the solvent isevaporated under reduced pressure, and the residue is separated bysilica gel thin layer chromatography (solvent; chloroform:methanol=30:1)to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine(27 mg) as colorless oil, MS (m/z): 435 (MH⁺).

EXAMPLE 26

A solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidineylmethyl)carbamoyl]-pyrimidine(82.48 g) and benzenesulfonic acid monohydrate (60.06 g) in methanol(1000 ml) is concentrated, and recrystallized from a mixture of methanoland acetone to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-2-pyrimidinylmethyl)carbamoyl]pyrimidinedibenzenesulfonate (121.8 g) as colorless crystals, m.p. 158.5-161.5° C.

EXAMPLE 27

A mixture of(S)-4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine(100 mg) obtained in Example 1-(4), 4-amino-1,3,5-trimethylpyrazole(47.9 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(58.7 mg), 1-hydroxybenzotriazole monohydrate (41.3 mg), andN,N-dimethylformamide (3 ml) is stirred at room temperature for 8 hours,and poured into aqueous sodium hydrogen carbonate solution. The mixtureis extracted with ethyl acetate, and the organic layer is washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent is evaporated under reduced pressure, and the residue ispurified by silica gel column chromatography (solvent;chloroform:methanol=5:1) to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5[-N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine(115 mg), MS (m/z): 500 (MH⁺).

EXAMPLE 28

(1) A solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (5.0g) in sulfuryl chloride (20 ml) is heated at 50° C. for one hour. Thereaction mixture is concentrated, and thereto is poured a saturatedaqueous sodium hydrogen carbonate solution. The mixture is extractedwith ethyl acetate, and the organic layer is washed with water andbrine, dried over sodium sulfate, and concentrated. The residue ispurified by silica gel flash column chromatography (solvent; ethylacetate=hexane=1:10) to quantitatively give2,4-dichloro-5-ethoxycarbonylpyrimidine (4.87 g) as yellow oil, MS(m/z): 220 (M⁺).

(2) To a solution of 2,4-dichloro-5-ethoxycarbonylpyrimidine (4.2 g)obtained in the above (1) and mercaptobenzene (2.30 g) in toluene (40ml) is added potassium carbonate (3.94 g) at 0° C., and the mixture isstirred at room temperature for one hour, stirred at 50° C. for onehour, and further stirred at 100° C. for 10 minutes. To the mixture ispoured water, and the mixture is extracted with ethyl acetate. Theorganic layer is washed with brine, dried over sodium sulfate, andconcentrated. The residue is purified by silica gel flash columnchromatography (solvent; ethyl acetate:hexane=1:20 methyl acetate:hexane=1:10) to give 2-chloro-4-phenylthio-5-ethoxycarbonylpyrimidine(4.16 g) as colorless crystals, MS (m/z): 295 (MH⁺).

(3) To a solution of 2-chloro-4-phenylthio-5-ethoxycarbonylpyrimidine(4.05 g) obtained in the above (2) in tetrahydrofuran (40 ml) are addedL-prolinol (1.66 g) and triethylamine (2.77 g), and the mixture isstirred at room temperature for 20 hours. Water is poured into thereaction mixture, and the mixture is extracted with ethyl acetate. Theorganic layer is washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel flash column chromatography (solvent; ethyl acetate:hexane=1:2) togive(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-ethoxycarbonylpyrimidine(4.16 g) as colorless viscous oil, MS (m/z): 360 (MH⁺).

(4) To a solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-ethoxycarbonylpyrimidine(4.10 g) obtained in the above (3) in ethanol (50 ml) is added a 4Naqueous sodium hydroxide solution (8.6 ml), and the mixture is stirredat room temperature for 15 hours. To the reaction solution is added a10% aqueous citric acid solution (30 ml) until the solution becomes weakacidic, and the mixture is extracted with ethyl acetate. The organiclayer is washed with water and brine, dried over sodium sulfate, andconcentrated to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-carboxypyrimidine(3.65 g) as colorless crystals, MS (m/z): 330 (M−H)⁻.

(5) A mixture of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-carboxypyrimidine(2.55 g) obtained in the above (4), 2-aminomethylpyrimidine (1.09 g),1,2-dichloroethane (1.77 g) and 1-hydroxybenzotriazole (1.25 g) inN,N-dimethylformamide (40 ml) is stirred at room temperature for 16hours. To the mixture is poured water, and the mixture is extracted withethyl acetate. The organic layer is washed with water, a saturatedaqueous sodium hydrogen carbonate solution and brine, dried over sodiumsulfate, and concentrated to give pale yellow crystals (4.05 g), whichis further purified by silica gel flash column chromatography (solvent;ethyl acetate) to give2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidylmethyl)carbamoyl]pyrimidine(2.39 g) as colorless crystals, m.p., 154-156° C., IR (Nujol): 1633cm⁻¹, MS (m/z): 423 (MH⁺).

(6) To a solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine(100 mg) obtained in the above (5) in chloroform (3 ml) is addedm-chloroperbenzoic acid (70.1 mg) at 0° C., and the mixture is stirredat 0° C. for 30 minutes. To the mixture are added 3-chlorobenzylamine(50.3 mg) and triethylamine (48.0 mg) at 0° C., and the mixture isstirred at room temperature for 17 hours. To the mixture is pouredwater, and the mixture is extracted with chloroform. The organic layeris washed with brine, dried over sodium sulfate, and concentrated underreduced pressure to give yellow oil (169 mg), which is purified bysilica gel flash column chromatography (solvent; ethyl acetate), andtriturated with a mixture of ethyl acetate and hexane to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chlorobenzylamino)-5-[N-2-pyrimidylmethyl)carbamoyl]pyrimidine(95.3 mg) as colorless powder, m.p. 153-156° C., IR (Nujol): 3241, 1637cm⁻¹, MS (m/z): 454 (MH⁺).

(7) To a solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine(100 mg) obtained in the above (5) in chloroform (3 ml) is addedm-chloroperbenzoic acid (70%, 70.1 mg) at 0° C., and the mixture isstirred at 0° C. for 30 minutes. To the mixture are added4-methoxybenzylamine (48.8 mg) and triethylamine (48.0 mg) at 0° C., andthe mixture is stirred at room temperature for 20 minutes. To themixture is poured water, and the mixture is extracted with chloroform,and the organic layer is washed with brine, dried over sodium sulfate,and concentrated to give a yellow oil (143 mg), which is purified bysilica gel flash column chromatography (solvent; ethyl acetate) to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(4-methoxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine(88.2 mg) as colorless powder, IR (Neat): 3296, 1633 cm⁻¹, MS (m/z): 450(MH⁺).

EXAMPLE 29

(1) A solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine(10.0 mg) in tetrahydro-furan (1.0 ml) obtained in Example 2 (3) istreated with a 1.6M solution of n-butyl lithium in hexane (83 μl) at−78° C. for 3 minutes, and thereto is added an aqueous sodium hydrogencarbonate solution. The reaction mixture is extracted with ethyl acetateto give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxypentyl)pyrimidine(13.7 mg) as oil.

(2)(S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxypentyl)pyrimidineobtained in the above is treated with manganese dioxide (25 mg) at roomtemperature, and thereto is added gradually additional manganese dioxide(100 mg), and the mixture is stirred overnight. The reaction mixture isheated under reflux for 5 hours, and the insoluble materials are removedby filtration. The filtrate is concentrated under reduced pressure, andseparated with preparative thin layer chromatography to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-pentanoylpyrimidine(5.8 mg) as colorless oil, MS (m/z): 433 (MH⁺).

EXAMPLES 30-83

The corresponding starting compounds are treated in a similar manner togive the compounds as listed in the following Table 4.

TABLE 4

Ex. No.

R⁰ R¹ Physicochemical properties 30

Cl

M.p. 210-214° C. 31

Cl

Amorphous MS(m/z): 517(MH⁺) 32

Cl

Amorphous MS(m/z): 503(MH⁺) 33

Cl

Amorphous MS(m/z): 538(MH⁺) 34

Cl

HCl salt M.p. 223-226° C. 35

Cl

Amorphous MS(m/z): 513(MH⁺) 36

Cl

Amorphous MS(m/z): 504(MH⁺) 37

Cl

MS(m/z): 524(MH⁺) 38

Cl

Amorphous MS(m/z): 524(MH⁺) 39

Cl

Foam MS(m/z): 490(MH⁺) 40

Cl

Amorphous MS(m/z): 539(MH⁺) 41

Cl

Amorphous MS(m/z): 528(MH⁺) 42

Cl

Amorphous MS(m/z): 500(MH⁺) 43

Cl

Amorphous MS(m/z): 527(MH⁺) 44

Cl

Amorphous MS(m/z): 468(MH⁺) 45

Cl

M.p. 220-222° C. 46

NO₂

Amorphous MS(m/z): 523(MH⁺) 47

NO₂

M.p. 188-190° C. 48

Cl

Amorphous MS(m/z): 518(MH⁺) 49

Cl

Amorphous MS(m/z): 532 (MH⁺) 50

Cl

M.p. 179-183° C. 51

Cl

Amorphous MS(m/z): 518(MH⁺) 52

Cl

Powder (HCl) MS(m/z): 518(MH⁺) 53

Cl

Amorphous MS(m/z): 520(MH⁺) 54

Cl

Powder (HCl) MS(m/z): 537(MH⁺) 55

Cl

Amorphous MS(m/z): 543(MH⁺) 56

Cl

M.p. 181-183° C. 57

Cl

Powder (HCl) MS(m/z): 496(MH⁺) 58

Cl

M.p. 199-200° C. 59

NO₂

M.p. 209.5-211.5° C. 60

Cl

M.p. 228-230.5° C. 61

Cl

Amorphous MS(m/z): 524(MH⁺) 62

Cl

Amorphous MS(m/z): 522(MH⁺) 63

Cl

Amorphous MS(m/z): 563(MH⁺) 64

Cl

Amorphous MS(m/z): 489(MH⁺) 65

Cl

Amorphous MS(m/z): 520(MH⁺) 66

Cl

M.p. 176-180° C. 67

CN

Powder (HCl) MS(m/ z): 543 (MH⁺) 68

Cl

M.p. 143-145° C. 69

Cl

Powder (HCl) MS(m/z): 504(MH⁺) 70

Cl

M.p. 130° C. 71

CN

Powder (HCl) MS(m/z): 474(MH⁺) 72

Cl

Amorphous MS(m/z): 519(MH⁺) 73

CN

Powder (HCl) MS(m/z): 481(MH⁺) 74

Cl

M.p. 116-119° C. 75

Cl

M.p. 159-161° C. 76

Cl

Powder (HCl) MS(m/z): 506(MH⁺) 77

Cl

Amorphous MS(m/z): 563(MH⁺) 78

Cl

Powder (HCl) MS(m/z): 497(MH⁺) 79

Cl

M.p. 210-214° C. 80

Cl

M.p. 149-151.5° C. 81

NO₂

Amorphous MS(m/z): 495(MH⁺) 82

Cl

M.p. 215° C. 83

Cl

M.p. 151-152° C.

EXAMPLES 84-86

The corresponding starting compounds are treated in a similar manner togive the compounds as listed in the following Table 5.

TABLE 5

Ex. No. R⁸ R¹ Physico- chemical properties 84

Foam MS(m/z): 470(MH⁺) 85

Powder MS(m/z): 488(MH⁺) 86

Powder MS(m/z): 468(MH⁺)

EXAMPLE 87

A mixture of(S)-2-carboxy-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine(80 mg) obtained in Example 22 (5), 2-aminomethyl-4-methylmorpholine(31.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(43 mg), 1-hydroxybenzotriazole (30.3 mg) in N,N-dimethylformamide (3ml) is stirred at room temperature for 18 hours. To the reaction mixtureis poured water, and the mixture is extracted with ethyl acetate. Theextract is washed with water, a saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel flesh column chromatography (solvent; ethyl acetate) to give(S)-2-[N-(4-methyl-2-morpholinyl)methylcarbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine(80.5 mg), MS (m/z): 505 (MH⁺), IR (Nujol): 3295, 1635 cm⁻¹.

EXAMPLE 88-91

The corresponding starting compounds are treated in a similar manner togive the compounds as listed in the following Table 6.

TABLE 6

Ex. No.

R¹ Physicochemical properties 88

M.p. 177-179° C. MS(m/z): 490(MH⁺) 89

M.p. 167-169° C. MS(m/z): 512(MH⁺) 90

M.p. 140.5-141.5° C. 91

Amorphous MS(m/z): 527(MH⁺)

EXAMPLE 92-145

The corresponding starting compounds are treated in a similar manner togive the compounds as listed in the following Table 7.

TABLE 7

Ex. No.

R¹ Physiochemical properties 92

Powder MS(m/z): 475(MH⁺) 93

Powder MS(m/z): 509(MH⁺) 94

Amorphous MS(m/z): 512(MH⁺) 95

M.p. 150-152° C. 96

M.p. 162-163° C. 97

Amorphous MS(m/z): 486(MH⁺) 98

Amorphous MS(m/z): 484(MH⁺) 99

Amorphous MS(m/z): 483(MH⁺) 100

Amorphous MS(m/z): 497(MH⁺) 101

M.p. 148-150° C. 102

Amorphopus MS(m/z): 512(MH⁺) 103

M.p. 210-213° C. 104

M.p. 195-198° C. 105

Amorphous MS(m/z): 498(MH⁺) 106

M.p. 232-235° C. 107

M.p. 207-208° C. 108

Amorphous MS(m/z): 547(MH⁺) 109

Amorphous MS(m/z): 501(MH⁺) 110

M.p. 172-173° C. 111

M.p. 145-147° C. 112

Amorphous MS(m/z): 497(MH⁺) 113

M.p. 148-150° C. 114

M.p. 217-219° C. 115

Amorphous MS(m/z): 484(MH⁺) 116

Amorphous MS(m/z): 514(MH⁺) 117

Amorphous MS(m/z): 568(MH⁺) 118

M.p. 217-220° C. 119

M.p. 212-214° C. 120

Amorphous MS(m/z): 514(MH⁺) 121

Amorphous MS(m/z): 488(MH⁺) 122

M.p. 142-144° C. 123

Amorphous MS(m/z): 472(MH⁺) 124

Amorphous MS(m/z): 497(MH⁺) 125

M.p. 143-146° C. 126

Amorphous MS(m/z): 514(MH⁺) 127

Amorphous MS(m/z): 498(NH⁺) 128

Amorphous MS(m/z): 513(MH⁺) 129

M.p. 101-103° C. 130

M.p. 215-217° C. 131

M.p. 180-183° C. 132

Oil MS(m/z): 482(MH⁺) 133

M.p. 176-179° C. 134

M.p. 224-227° C. 135

Amorphous MS(m/z): 500(MH⁺) 136

M.p. 177-180° C. 137

Powder MS(m/z): 486(MH⁺) 138

Powder MS(m/z): 486(MH⁺) 139

Powder MS(m/z): 500(MH⁺) 140

Amorphous MS(m/z): 499(MH⁺) 141

Amorphous MS(m/z): 448(MH⁺) 142

Amorphous MS(m/z): 503(MH⁺) 143

M.p. 112-114° C. 144

Amorphous MS(m/z): 512(MH⁺) 145

M.p. 123-125° C.

EXAMPLE 146

The corresponding starting compounds are treated in a similar manner togive the compound of the following formula as foam, MS (m/z): 464 (MH⁺).

EXAMPLE 147

The corresponding starting compounds are treated in a similar manner togive the compound of the following formula, m.p. 140-144° C.

EXAMPLE 148

To a solution of(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]-pyrimidine(307 mg) obtained in Example 1-(5) in methylene chloride (6 ml) is addeddropwise boron bromide (300 μl) under ice-cooling. The reaction mixtureis stirred at 0° C. for 4 hours, and thereto is added methanol, and thena saturated aqueous sodium hydrogen carbonate solution underice-cooling. The mixture is extracted with a mixture of ethyl acetateand tetrahydrofuran, and the organic layer is washed successively withwater and brine. The mixture is dried over sodium sulfate, andconcentrated under reduced pressure to give a slightly brown amorphous(227 mg). The resultant is suspended in chloroform, and the resultinginsoluble materials are removed by filtration. The filtrate is subjectedto silica gel column chromatography, and further purified by NH-silicagel column chromatography to give(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-hydroxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine(129 mg) as a colorless foam, MS (m/z): 470 (MH⁺), IR (Nujol): 3279,1632, 1593, 1569, 1518, 1463 cm⁻¹.

EXAMPLE 149

(1) A suspension of2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine(2.00 g) obtained in Example 1 (1) in dimethylsulfoxide (10 ml) istreated with 10% aqueous sodium hydroxide solution (10 ml) at roomtemperature. To the reaction mixture is added dimethylsulfoxide (5 ml),and the mixture is stirred at room temperature overnight. To theresulting colorless solution is added citric acid until the solutionbecomes acidic. To the solution is added an excess amount of water(about 50 ml), and the resulting precipitates are collected byfiltration. The precipitates are washed with isopropyl alcohol andisopropyl ether successively, and dried under reduced pressure to give2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine(1.864 g) as pale yellow impalpable powder, m.p. 238-240° C. (dec.).

(2) To a suspension of4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-methylthiopyrimidine (200mg) in methylene chloride (5 ml) are added oxalyl chloride (150 mg) andN,N-dimethylformamide, and the mixture is stirred at room temperaturefor 30 minutes, and concentrated. To a suspension of the resulting acidchloride compound and 5-aminopyrimidine (84.0 mg) in methylene chloride(5 ml) is added dimethylaminopyridine (144 mg) at room temperature, andthe mixture is stirred at room temperature. To the mixture is pouredwater, and the mixture is extracted with ethyl acetate. The extract iswashed with a saturated aqueous sodium hydrogen carbonate solution,water and brine, dried over sodium sulfate, and concentrated. Theresidue is triturated with a mixture of ethyl acetate and n-hexane togive4-(3-chloro-4-methoxybenzylamino)-5-(5-pyrimidinylaminocarbonyl)-2-methylthiopyrimidine(216 mg 238-240° C., IR (Nujol): 3251, 1666 cm⁻¹, MS (m/z): 416 (M⁺).

(3) To a suspension of the compound (150 mg) obtained in the above (2)in chloroform (10 ml) is added m-chloroperbenzoic acid (107 mg) at 0°C., and the mixture is stirred at 0° C. for one hour, and stirred atroom temperature for one hour. To the mixture is addedm-chloroperbenzoic acid (53 mg) at 0° C., and the mixture is stirred at0° C. for 30 minutes. To the mixture are added L-prolinol (43.7 mg) andtriethylamine (72.9 mg) at 0° C., and the mixture is stirred at roomtemperature for 20 hours. To the mixture is poured water, and themixture is extracted with chloroform. The organic layer is washed withbrine, dried over sodium sulfate, and concentrated under reducedpressure to give yellow viscous oil (201 mg), which is purified byNH-silica gel flash column chromatography (solvent; ethyl acetate),washed with a mixture of ethyl acetate and hexane to give(S)-4-(3-chloro-4-methoxybenzylamino)-5-(5-pyrimidinylaminocarbonyl)-2-(hydroxymethyl-1-pyrrolidinyl)pyrimidine(81 mg) as colorless needles, m.p. 192-195° C., IR (Nujol): 3279, 1669cm⁻¹, MS (m/z): 470 (MH⁺).

EXAMPLES 150-157

The corresponding starting compounds are treated in a similar manner asin Example 149 to give the compounds as listed in the following Table 8.

TABLE 8

Ex. No.

R¹ Physiochemical properties 150

Powder MS(m/z): 469(MH⁺) 151

Powder MS(m/z): 470(MH⁺) 152

M.p. 182-185° C. 153

M.p. 176-178° C. 154

Powder MS(m/z): 487(MH⁺) 155

M.p. 161-163° C. 156

Powder MS(m/z): 513(MH⁺) 157

Powder MS(m/z): 498(MH⁺)

EXAMPLE 158

(1) A suspension of4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-methylthiopyrimidine(154.0 mg) obtained in Example 149 (1) in methylene chloride (5 ml) istreated with oxalyl chloride (119 μl) at room temperature, and theretois added N,N-dimethylformamide. The mixture is stirred for one hour, andthe solvent is evaporated under reduced pressure. The residue is treatedwith ether, and kept in a refrigerator overnight. The volatile materialsare removed under reduced pressure, and the residue is treated with anexcess amount of diazomethane at 0° C., and kept in a refrigeratorovernight. The reaction is quenched with methanol, and the mixture ispurified by silica gel chromatography (solvent; hexane:ethylacetate=2:1) to give4-(3-chloro-4-methoxybenzylamino)-5-(diazomethylcarbonyl)-2-methylthiopyrimidine(21.5 mg) as pale yellow solid, IR (Nujol); 3277, 2115, 1607, 1567,1461, 1377, 1357, 1141 cm⁻¹, MS (m/z): 364 (MH⁺), m.p. 162-165° C.(dec.).

(2) A suspension of the compound obtained in the above (1) (16.5 mg) inmethanol (3 ml) is treated with toluenesulfonic acid monohydrate (16.5mg) at room temperature. The solvent is evaporated under reducedpressure, and the residue is purified by preparative TLC (solvent;hexane:ethyl acetate=2:1) to give4-(3-chloro-4-methoxybenzylamino)-5-(methoxymethylcarbonyl)-2-methylthiopyrimidine(11.0 mg) as colorless oil.

(3) A solution of the compound (11.0 mg) obtained in the above (2) inchloroform (1 ml) is treated with m-chloroperbenzoic acid (7.4 mg) at 0°C. The mixture is treated with triethylamine (8.3 μl) and L-prolinol (36mg) at room temperature, and the reaction mixture is stirred overnight.The reaction mixture is diluted with ethyl acetate, washed with asaturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous sodium chloride solution, and dried over sodium sulfate. Theresidue is purified by preparative TLC (solvent; chloroform:ethylacetate=1:1) to give(S)-4-(3-chloro-4-methoxybenzylamino)-5-(methoxymethylcarbonyl)-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine(8.5 mg) as colorless oil, MS (m/z): 421 (MH⁺).

INDUSTRIAL APPLICABILITY

The compound (I) of the present invention and a pharmaceuticallyacceptable salt thereof exhibit excellent PDE V inhibitory activities,and they are useful pharmaceutical compounds for the prophylaxis ortreatment of penile erectile dysfunction, etc.

What is claimed is:
 1. An aromatic nitrogen-containing 6-membered cycliccompound of the formula (I):

wherein Ring A is a substituted or unsubstituted nitrogen-containingheterocyclic group; R¹ is a substituted or unsubstituted lower alkylgroup, a group of the formula: —NH—Q—R³ in which R³ is a substituted orunsubstituted nitrogen containing heterocyclic group, and Q is a loweralkylene group or a single bond, or a group of the formula: —NH—R⁴ inwhich R⁴ is a substituted or unsubstituted cycloalkyl group; R² is asubstituted or unsubstituted aryl group; Y is a group of the formula:═CH—, and Z is a group of the formula: ═N—, or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1, whereinthe nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5-or 6-membered nitrogen-containing heteromonocyclic group or a 8- to10-membered nitrogen-containing heterobicyclic group, and thesubstituent of the above “substituted or unsubstitutednitrogen-containing heterocyclic group” is selected from the groupconsisting of (1) a lower alkyl group, (2) a hydroxy-substituted loweralkyl group, (3) a formyl group, (4) an oxo group, (5) an amino group,(6) a hydroxy group, (7) a lower alkoxycarbonyl group, and (8) apyrimidinyl group substituted by (i) a benzylamino group substituted bya halogen atom and a lower alkoxy group, and (ii) a cycloalkylcarbamoylgroup substituted by a hydroxy group, R¹ is a lower alkyl group whichmay optionally be substituted by a group selected from the groupconsisting of a lower alkoxy group, a hydroxy group, a morpholinylgroup, a lower alkylsulfonyl group, a di-(lower alkyl)phosphino group, adi-(lower alkyl)amino group, a pyrimidinyl-substituted lower alkylaminogroup, a pyridyl group, a pyridylamino group and a loweralkyl-substituted piperazinyl group, a group of the formula: —NH—Q—R³,or a group of the formula: —NH—R⁴, the nitrogen-containing heterocyclicgroup of the “substituted or unsubstituted nitrogen-containingheterocyclic group” for R³ is a 5- or 6-membered nitrogen-containingheteromonocyclic group or a 8- to 10-membered nitrogen-containingheterobicyclic group, and the substituent of the above “substituted orunsubstituted nitrogen-containing heterocyclic group” is selected fromthe group consisting of a lower alkyl group, a hydroxy-substituted loweralkyl group, an oxo group, an amino group, a di-(lower alkyl)aminogroup, a lower alkanoyl group and a cyano-substituted lower alkyl group,R⁴ is a cycloalkyl group being substituted by a group selected from thegroup consisting of hydroxy group, a lower alkoxy group and apyrimidinyloxy group, R² is a phenyl group being substituted by a groupselected from the group consisting of a lower alkoxy group, a halogenatom, a cyano group, a nitro group, a hydroxy group and a lower alkylgroup.
 3. The compound according to claim 2, wherein thenitrogen-containing heterocyclic group of the substituted orunsubstituted nitrogen-containing heterocyclic group for Ring A is a 5-or 6-membered nitrogen-containing heteromonocyclic group of the formula:

or a nitrogen-containing heterobicyclic group of the following formulawherein the above-mentioned 5- or 6-membered nitrogen-containingheteromonocyclic group and a 5- or 6-membered cyclic group are fused:

and the nitrogen-containing heterocyclic group of the substituted orunsubstituted nitrogen-containing heterocyclic group for R³ is anon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or an aromatic nitrogen-containing heterocyclic group of the formula:


4. The compound according to claim 1, wherein the nitrogen-containingheterocyclic group of the “substituted or unsubstitutednitrogen-containing heterocyclic group” for Ring A is a 5- or 6-memberednitrogen-containing heteromonocyclic group or a 8- to 10-memberednitrogen-containing heterobicyclic group, and the substituent of theabove “substituted or unsubstituted nitrogen-containing heterocyclicgroup” is selected from the group consisting of a lower alkyl group, ahydroxy-substituted lower alkyl group, a formyl group and an oxo group,R¹ is a lower alkyl group which may optionally be substituted by a groupselected from the group consisting of a lower alkoxy group and amorpholinyl group, a group of the formula: —NH—Q—R³, or a group of theformula: —NH—R⁴, the “substituted or unsubstituted nitrogen-containingheterocyclic group” for R³ is a 5- or 6-membered nitrogen-containingheteromonocyclic group which may optionally be substituted by a loweralkyl group, R⁴ is a cycloalkyl group being substituted by a groupselected from the group consisting of hydroxy group and a lower alkoxygroup, R² is a phenyl group being substituted by a group selected fromthe group consisting of a lower alkoxy group, a halogen atom and a cyanogroup.
 5. The compound according to claim 4, wherein thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5-or 6-membered non-aromatic nitrogen-containing heteromonocyclic group ofthe formula:

or a nitrogen-containing heterobicyclic group of the following formulawherein the above-mentioned 5- or 6-membered non-aromaticnitrogen-containing heteromonocyclic group and a 5- or 6-memberedaromatic nitrogen-containing heteromonocyclic group are fused:

the nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is anon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or an aromatic nitrogen-containing heteromonocyclic group of theformula:


6. The compound according to claim 1, wherein Ring A is a group of theformula:

R¹ is a lower alkyl group, a lower alkoxy-substituted lower alkyl group,a morpholinyl-substituted lower alkyl group, a group of the formula:—NH—Q—R³, or a group of the formula: —NH—R⁴, R³ is a group of theformula:

R⁴ is a group of the formula:

and R² is a group of the formula:


7. The compound according to claim 1, wherein the nitrogen-containingheterocyclic group of the “substituted or unsubstitutednitrogen-containing heterocyclic group” for Ring A is a 5- or 6-memberednitrogen-containing heteromonocyclic group or a 8- to 10-memberednitrogen-containing heterobicyclic group, and the substituent of theabove “substituted or unsubstituted nitrogen-containing heterocyclicgroup” is a group selected from the group consisting of a lower alkylgroup, a hydroxy-substituted lower alkyl group, a formyl group and anoxo group, R¹ is a lower alkoxy-substituted lower alkyl group, a groupof the formula: —NH—Q—R³, or a group of the formula: —NH—R⁴, the“substituted or unsubstituted nitrogen-containing heterocyclic group”for R³ is a 5- or 6-membered nitrogen-containing heteromonocyclic groupwhich may optionally be substituted by a lower alkyl group, R⁴ is ahydroxy-substituted cycloalkyl group, and R² is a phenyl group beingsubstituted by a group selected from the group consisting of a loweralkoxy group and a halogen atom.
 8. The compound according to claim 7,wherein the nitrogen-containing heterocyclic group of the “substitutedor unsubstituted nitrogen-containing heterocyclic group” for Ring A is a5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic groupof the formula:

a group of the formula:

the nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is anon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or an aromatic nitrogen-containing heteromonocyclic group of theformula:


9. The compound according to claim 1, wherein Ring A is a group of theformula:

R¹ is a lower alkoxy-substituted lower alkyl group, a group of theformula: —NH—Q—R³, or a group of the formula: —NH—R⁴, R³ is a group ofthe formula:

R⁴ is a group of the formula:

and R² is a group of the formula:


10. The compound according to claim 1, wherein the nitrogen-containingheterocyclic group of the “substituted or unsubstitutednitrogen-containing heterocyclic group” for Ring A is a 5- or 6-memberednitrogen-containing heteromonocyclic group or a 8- to 10-memberednitrogen-containing heterobicyclic group, and the substituent of theabove “substituted or unsubstituted nitrogen-containing heterocyclicgroup” is a hydroxy-substituted lower alkyl group, R¹ is a group of theformula: —NH—Q—R³, the “substituted or unsubstituted nitrogen-containingheterocyclic group” for R³ is a 5- or 6-membered nitrogen-containingheteromonocyclic group which may optionally be substituted by a loweralkyl group, and R² is a phenyl group being substituted by a groupselected from the group consisting of a lower alkoxy group and a halogenatom.
 11. The compound according to claim 10, wherein thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5-or 6-membered non-aromatic nitrogen-containing heteromonocyclic group ofthe formula:

or a group of the formula:

the nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is anon-aromatic nitrogen-containing heteromonocyclic group of the formula:

or an aromatic nitrogen-containing heteromonocyclic group of theformula:


12. The compound according to claim 1, wherein Ring A is a group of theformula:

R¹ is a group of the formula: —NH—Q—R³, R³ is a group of the formula:

and R² is a group of the formula:


13. The compound according to claim 1, wherein said compound is selectedfrom the group consisting of:(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazine;(S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine;and2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-yl)pyrazine;or a pharmaceutically acceptable salt thereof.
 14. The compoundaccording to claim 13, wherein the compound is(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazine,or a pharmaceutically acceptable salt thereof.
 15. The compound of claim13, wherein the compound is(S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine.16. A pharmaceutical composition, which contains as an active ingredientthe compound as set forth in any one of claims 1-12 and 13-15 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier therefor.
 17. A method for treatment of penileerectile dysfunction, which comprises administering to a patient in needthereof an effective amount of the compound as set forth in any one ofclaims 1-12 and 13-15, or a pharmaceutically acceptable salt thereof.18. A method for treatment of pulmonary hypertension, which comprisesadministering to a patient in need thereof an effective amount of thecompound as set forth in any one of claims 1-12 and 13-15 or apharmaceutically acceptable salt thereof.
 19. A method for treatment ofdiabetic gastroparesis, which comprises administering to a patient inneed thereof an effective amount of the compound as set forth in any oneof claims 1-12 and 13-15, or a pharmaceutically acceptable salt thereof.